Children residing in holoendemic regions of malaria transmission, such as western Kenya, are at an increased risk for developing life-threatening complications due to severe malarial anemia (SMA). Our recent findings in this area illustrate that the highest rates of SMA-associated morbidity and mortality occur in children between birth and 2 years of age. Therefore, we will investigate the genetic and immunologic mechanisms of SMA in young children residing in Kisumu, Kenya. Since effective cell-mediated immunity is required for controlling malaria infection, we will focus on defining the role of cytokines [interleukin (IL )-12, tumor necrosis factor (TNF)-alpha, macrophage migration inhibitory factor (MIF), IL-10 and transforming growth factor (TGF)-beta1], and effector molecules [nitric oxide (NO) and prostaglandin (PG)-E2] in the immunopathogenesis of SMA. The goals of this proposal are: 1) to identify unique profiles of cytokine and effector molecule gene expression associated with the development and outcome of SMA, 2) to determine if polymorphisms in the cytokine and effector molecule genes lead to disequilibrium in the cytokine balance that affects the clinical course and outcome of SMA, and 3) to identify novel patterns of gene expression associated with the immunopathogenesis of SMA. The overall goal of this proposal is to identify the immunomodulatory genes, whose critical patterns of expression underlie disease susceptibility to SMA. Successful completion of this project, that takes into account the complex genetic, inflammatory, and clinical factors that promote malarial anemia, will offer important information for the future development and testing of malaria vaccine candidates.